General and Comparative Endocrinology xxx (2014) xxx–xxx Contents lists available at ScienceDirect General and Comparative Endocrinology journal homepage: www.elsevier.com/locate/ygcen Review Regulation of TRP channels by steroids: Implications in physiology and diseases ⇑ Ashutosh Kumar, Shikha Kumari, Rakesh Kumar Majhi, Nirlipta Swain, Manoj Yadav, Chandan Goswami School of Biology, National Institute of Science Education and Research, Sachivalaya Marg, Bhubaneswar, Orissa 751005, India article info abstract Article history: While effects of different steroids on the gene expression and regulation are well established, it is proven Available online xxxx that steroids can also exert rapid non-genomic actions in several tissues and cells. In most cases, these non-genomic rapid effects of steroids are actually due to intracellular mobilization of Ca2+- and other ions Keywords: suggesting that Ca2+ channels are involved in such effects. Transient Receptor Potential (TRP) ion TRP channels channels or TRPs are the largest group of non-selective and polymodal ion channels which cause Ca2+- Steroids influx in response to different physical and chemical stimuli. While non-genomic actions of different Non-genomic action of steroids steroids on different ion channels have been established to some extent, involvement of TRPs in such Ca2+-influx functions is largely unexplored. In this review, we critically analyze the literature and summarize how Expression different steroids as well as their metabolic precursors and derivatives can exert non-genomic effects by acting on different TRPs qualitatively and/or quantitatively. Such effects have physiological repercus- sion on systems such as in sperm cells, immune cells, bone cells, neuronal cells and many others. Different TRPs are also endogenously expressed in diverse steroid-producing tissues and thus may have importance in steroid synthesis as well, a process which is tightly controlled by the intracellular Ca2+ con- centrations. Tissue and cell-specific expression of TRP channels are also regulated by different steroids. Understanding of the crosstalk between TRP channels and different steroids may have strong significance in physiological, endocrinological and pharmacological context and in future these compounds can also be used as potential biomedicine. Ó 2014 Elsevier Inc. All rights reserved. 1. Introduction receptors and ion channels involved in such responses are largely unknown. Nevertheless, identification of molecular candidates Steroid actions can be both genomic and non-genomic (i.e., involved in rapid steroid signaling events and understanding of rapid effects produced within minutes and which are independent the signaling events involved in such processes are important from of transcriptional or translational stimulation). In contrast to the a physiological, pharmacological and clinical perspective. In this well-established genomic effects, these non-genomic and rapid context, Transient Receptor Potential (TRP) ion channels (TRPs) effects of steroids are poorly understood, although such effects are relevant. have been noted in several systems including neurons. For exam- TRPs are a group of non-selective ion channels which mediate ple, very rapid effects of several neurosteroids on the neuronal sys- the transmembrane flux of Ca2+ (and other cations too) down an tem is well established. Notably, it has been observed that fast and electrochemical gradient, thereby increasing the intracellular Ca2+ non-genomic actions of steroids are dose-dependent, often revers- and Na+ concentration and causing cell depolarization. TRP chan- ible, stereo-specific and can be blocked by other signaling com- nels were first discovered in a Drosophila trp mutant, which had pounds suggesting that these steroids initiate specific biological a modified response to light (Minke, 1977; Montell et al., 1985). responses through specific signaling cascades (Gu and Moss, Subsequently members of the TRP family have been identified in 1996; Falkenstein et al., 2000). While a handful of reports suggest vertebrates, and other invertebrates and in lower eukaryotes such that these fast and non-genomic effects of steroids originate at the as yeast and fungi. However, so far TRPs or their exact homologs plasma membrane, the molecular mechanisms and the signaling have not been detected in plants. TRPs are classified on the basis events are not well understood. The molecular identities of the of their sequence homology and by the presence of specific signa- ture domains and motifs such as the TRP-domain, TRP-box motifs, ankyrin repeats, etc. (Clapham, 2003; Nilius and Owsianik, 2011). ⇑ Corresponding author. E-mail address: [email protected] (C. Goswami). The primary structure of all TRPs consists of six transmembrane http://dx.doi.org/10.1016/j.ygcen.2014.10.004 0016-6480/Ó 2014 Elsevier Inc. All rights reserved. Please cite this article in press as: Kumar, A., et al. Regulation of TRP channels by steroids: Implications in physiology and diseases. Gen. Comp. Endocrinol. (2014), http://dx.doi.org/10.1016/j.ygcen.2014.10.004 2 A. Kumar et al. / General and Comparative Endocrinology xxx (2014) xxx–xxx regions with a pore domain between the fifth and sixth transmem- mRNA and protein levels as well as duodenal TRPV6 expression brane region and both the N- and C-termini are intracellular. Based in rats (van Abel et al., 2002, 2003). In mice TRPV6 expression on amino acid sequence, homology with other TRP channels, and was induced after 17b-estradiol treatment (Lee and Jeung, 2007) the presence of specific structural features, the TRPs have been and in pregnant rat, expression of TRPV6 transcription appeared classified into 7 subfamilies, namely, TRPC (Canonical), TRPV to be solely controlled by progesterone (Lee et al., 2009). Estrogen (Vanilloid), TRPM (Melastatin), TRPA (Ankyrin), TRPP (Polycystin), in particular has also been shown to induce the expression of TRPML (Mucolipin) and TRPN (No Mechanoreceptor Potential C, TRPV1 channel in rats (Yan et al., 2007). In MCF-7 which is a breast NOMPC). cancer cell line, ERa has been shown to regulate the expression of In animals, TRP channels are ubiquitously expressed in almost TRPM8 (Chodon et al., 2010). all cell types and tissues, albeit at different levels. However, Often the expressions of different TRP channels in a given involvement of TRP channels in physiological functions and sen- tissue/cell are tightly controlled by the serum levels of different sory processes are relevant in multi-cellular as well as in unicellu- steroid hormones. For example, female sex hormones E2 and P4 lar organisms also. Most of the TRPs are selectively activated by alone or in combination can modulate the transcription of trp specific ligands and are polymodal in nature (Baez-Nieto et al., genes involved in physiological functions linked to pregnancy. 2011). TRP channels are regulated by multiple stimuli, both phys- The uterine expression of TRPV6 during the estrous cycle in ical and chemical and a few members of TRPs, namely TRPV1, rodents is modulated by steroid hormones and TRPV6 transcripts TRPV2, TRPV3, TRPV4, TRPM3, TRPM8, TRPA1 are thermosensitive. in the rat uterus is highly up-regulated by P4 at diestrus (Kim In most cases the chemical ligands are hydrophobic in nature and et al., 2006), while in mouse uterus TRPV6 mRNA is up-regulated several endogenous hydrophobic compounds (such as different lip- by E2 at estrus (Lee and Jeung, 2007). Uterine TRPV6 has increased ids) have been reported to activate or inhibit TRP channels (Holzer, expression during implantation and just prior to birth while it 2011). The complex polymodal regulation of TRP channels by intra- declines sharply following birth and during lactation, and is mainly cellular as well as extracellular components such as, specific lipids, regulated by serum concentrations of P4 or E2 in rat and mouse pH, ROS, NO, metal ions, interacting proteins, etc. and the multiple respectively (Lee et al., 2009). In rodents TRPV6 expression in the routes of regulation by phosphorylation-dephosphorylation and placenta initially follows the pattern of uterine expression, with other post-translational modifications, suggest that these channels an induction in the middle of gestation but not at the end of gesta- integrate multiple signaling events at the plasma membrane. In tion (Lee and Jeung, 2007). The species-specific regulation of TRPV6 this context, TRPs have been investigated for rapid signaling med- transcription in the uterus and placenta may be a consequence of iated by different steroids and may be an important group of the uterine calcium ion concentration required for successful molecular targets for the fast and non-genomic actions of different implantation of embryo and in rats P4 and PRs are important while steroids. Reports also suggest that expressions of TRPs are also con- in mice E2 and ERs are regulatory (Lee et al., 2009). trolled by different steroids as long-term effects. The crosstalk Several other TRP channels are also regulated by E2 and P4. For between steroids and TRPs may have crucial implications in sev- example, both E2 and P4 are involved in the regulation of trpm2 eral spheres such as in clinical, pharmacological, endocrinology, gene during the oestrous cycle of female rats. Changes in TRPM2 food safety, species conservation and several other aspects. The expression in stromal cells of the myometrium and endometrium present review will present the importance of TRPs in the signaling of mature rats during oestrous